It is well-documented that obesity is associated with resistance to insulin- stimulated glucose uptake and may ultimately lead to the development of non-insulin-dependent diabetes. As over 80% of insulin-stimulated glucose clearance is mediated by skeletal muscle, it is of importance to evaluate interventions that may improve insulin action in skeletal muscle. Recently, leptin, the product of the ob gene, has been shown to reduce fat mass, hyperglycemia and hyperinsulinemia. Of particular interest, chronic leptin administration increases insulin-stimulated glucose uptake and transport in normal and insulin-resistant rat skeletal muscle. However, there has been little evidence presented to data indicating the mechanism by which chronic leptin administration improves insulin-mediated glucose clearance. Therefore, there are several novel questions that will be addressed in the proposed investigations. In the first investigation we address if chronic leptin administration alters components of the insulin- signaling cascade in normal and insulin-resistant skeletal muscle. In the second investigation we address if alterations in lipid metabolism, following chronic leptin treatment, can account for improvements in glucose metabolism in insulin-resistant skeletal muscle. In the third investigation we attempt to further our understanding how insulin- mediated glucose regulation is improved by interventions that appear to have similar effects on obesity and skeletal muscle insulin-resistance. The proposed investigations incorporate the use of experimental procedures that will serve to enhance and further develop the depth and quality of research performed in my laboratory. In addition, student trainees working on the project will be exposed to and acquire laboratory skills that will promote their intellectual maturity and prepare them for research careers at universities, research institutes and the biomedical industry.